Little is known of the inflammatory mechanisms of chronic otitis media that lead to inner ear pathology. Therefore, the long-term goal of this research program is to identify and prevent the inflammatory processes by which chronic middle ear disease causes permanent cochlear damage. Preliminary studies have determined that acute and chronic middle ear inflammation induces cytokine gene expression by inner ear tissues. This inner ear gene expression profile includes inflammatory mediators, as well as tissue remodeling cytokines, such as fibroblast growth factors (FGF), bone morphogenetic proteins (BMP), vascular endothelial growth factor (VEGF), etc. This has provided new insights into the inflammatory mechanisms by which otitis media causes permanent cochlear changes, such as sensorineural hearing loss. Our preliminary studies also showed that steroid treatments can reverse these cochlear problems if caught early enough. Therefore, our underlying hypothesis is that the sensorineural hearing loss and cochlear tissue remodeling that occurs in chronic otitis media can be prevented or reversed if the proper therapeutic treatment is targeted to the specific inflammatory process that is active. The proposed study will characterize the pathologic mechanisms of inner ear gene expression due to acute and chronic middle ear inflammation and assess how these pathologic processes can be controlled by targeted therapies. The proposed studies will utilize BALB/c mice inoculated with heat-killed bacteria (acute otitis media) and C3H/HeJ mice defective for Toll-like receptor 4 (chronic otitis media). Aim 1 will determine the inner ear cytokine genes expressed during the progression from acute to chronic middle ear inflammation; Aim 2 will characterize the genes underlying inner ear tissue remodeling during the progression from acute to chronic middle ear inflammation; Aim 3 will exploit different toll-like receptor knockout mice to determine which bacterial components and inflammatory pathways regulate specific cochlear cytokine genes for inflammation and remodeling, and Aim 4 will develop the most appropriate interventional therapies to control these phases of inner ear gene expression during the progression from acute to chronic middle ear inflammation. These studies will identify the specific gene expression mechanisms underlying cochlear pathology due to middle ear inflammation and develop therapies that can be targeted to the relevant immune processes. This will lay important groundwork for the development of better clinical treatment options for children and adults with chronic otitis media to prevent permanent sensorineural hearing loss and other cochlear pathology. A study is proposed to evaluate the mechanisms by which chronic middle ear inflammation leads to cochlear pathology. Mouse models for acute and chronic middle ear disease will assess the role of different bacterial components on cytokine gene expression in the middle and inner ear and how this expression changes as inflammation transitions from an innate immune response to a cell-mediated adaptive immune response. Finally, various treatments will be targeted to these specific phases of inflammation to suppress the immune responses and protect the inner ear from permanent damage.